Alpha-Naphthoflavone as a Novel Scaffold for the Design of Potential Inhibitors of the APH(3')-IIIa Nucleotide-Binding Site of Enterococcus faecalis.

The spread of nosocomial infections caused by antibiotic-resistant Enterococcus faecalis is one of the major threats to global health at present. While aminoglycosides are often used to combat these infections, their effectiveness is reduced by various resistance mechanisms, including aminoglycoside modifying enzymes, and there are currently no drugs to inhibit these enzymes. To address this issue, this study was conducted to identify potential aminoglycoside adjuvants from a database of 462 flavones. The affinity of these molecules with the nucleotide-binding site (NBS) of aminoglycoside phosphotransferase type IIIa of E. faecalis (EfAPH(3')-IIIa) was evaluated, and the five molecules with the highest binding energies were identified. Of these, four were naphthoflavones, suggesting that their backbone could be useful in designing potential inhibitors. The highest-ranked naphthoflavone, 2-phenyl-4H-benzo[h]chromen-4-one, was modified to generate two new derivatives (ANF2OHC and ANF2OHCC) to interact with the NBS similarly to adenine in ATP. These derivatives showed higher binding free energies, better stability in molecular dynamics analysis and superior pharmacokinetic and toxicological profiles compared to the parent molecule. These findings suggest that these alpha-naphthoflavone derivatives are potential inhibitors of EfAPH(3')-IIIa and that this core may be a promising scaffold for developing adjuvants that restore the sensitivity of aminoglycosides.

In Silico and In Vitro Identification of 1,8-Dihydroxy-4,5-dinitroanthraquinone as a New Antibacterial Agent against Staphylococcus aureus and Enterococcus faecalis.

Increasing rates of bacterial resistance to antibiotics are a growing concern worldwide. The search for potential new antibiotics has included several natural products such as anthraquinones. However, comparatively less attention has been given to anthraquinones that exhibit functional groups that are uncommon in nature. In this work, 114 anthraquinones were evaluated using in silico methods to identify inhibitors of the enzyme phosphopantetheine adenylyltransferase (PPAT) of Staphylococcus aureus, Enterococcus faecalis, and Escherichia coli. Virtual screenings based on molecular docking and the pharmacophore model, molecular dynamics simulations, and free energy calculations pointed to 1,8-dihydroxy-4,5-dinitroanthraquinone (DHDNA) as the most promising inhibitor. In addition, these analyses highlighted the contribution of the nitro group to the affinity of this anthraquinone for the nucleotide-binding site of PPAT. Furthermore, DHDNA was active in vitro towards Gram-positive bacteria with minimum inhibitory concentration (MIC) values of 31.25 µg/mL for S. aureus and 62.5 µg/mL for E. faecalis against both antibiotic-resistant isolates and reference strains but was ineffective against E. coli. Experiments on kill-time kinetics indicated that, at the tested concentrations, DHDNA produced bacteriostatic effects on both Gram-positive bacteria. Overall, our results present DHDNA as a potential PPAT inhibitor, showing antibacterial activity against antibiotic-resistant isolates of S. aureus and E. faecalis, findings that point to nitro groups as key to explaining these results.

Experiencia y manejo de dos casos de gangrena de Fournier en pacientes pediátricos en el Instituto Nacional de Salud del Niño - San Borja / Experience and management of two cases of fournier's gangrene in pediatric patients at the Instituto Nacional de Salud del Niño - San Borja, Lima, Peru

RESUMEN La gangrena de Fournier es una patología que se encuentra predominantemente en varones adultos y extremadamente rara en niños. Se han descrito múltiples factores predisponentes en los niños, incluyendo la circuncisión, la dermatitis del pañal, la presencia de abscesos, traumatismos anorrectales y deficiencias inmunológicas. Los signos y síntomas característicos incluyen edema e hiperemia de rápida evolución en la región perineal acompañados de dolor intenso y fiebre. Una vez que se diagnostica la gangrena de Fournier, se debe instaurar tratamiento de forma inmediata, antibióticos endovenosos de amplio espectro y debridamiento quirúrgico temprano del tejido desvitalizado. A continuación presentamos un reporte de casos que incluye las características clínicas y epidemiológicas de dos pacientes pediátricos con gangrena de Fournier que recibieron tratamiento médico y quirúrgico en el Instituto Nacional de Salud del Niño de San Borja.

ABSTRACT Fournier's gangrene is a condition mainly found in adults and it very rarely occurs in children. Multiple predisposing factors have been identified for children, including circumcision, diaper dermatitis, the occurrence of abscesses, anorectal trauma, and immune deficiency. Characteristic signs and symptoms include rapidly progressing edema and hyperemia in the perineal region, accompanied by intense pain and fever. Once Fournier's gangrene is diagnosed, therapy must be immediately instituted, using wide spectrum intravenous antibiotics and early surgical debridement of devitalized tissues. We present a case report including clinical and epidemiological characteristics of two pediatric patients with Fournier's gangrene who received medical and surgical therapy at the Instituto Nacional de Salud del Niño in San Borja, Lima, Peru.

Use of oral fluralaner for the treatment of Psoroptes cuniculi in 15 naturally infested rabbits.

BACKGROUND: Psoroptes cuniculi, a nonburrowing ear mite, is a common ectoparasite of rabbits. Constant irritation of the auditory canal by the presence of this mite can lead to otitis externa or otoacariasis. OBJECTIVE: The goal of this study was to evaluate the effect of fluralaner on rabbits naturally infested with P. cuniculi and exhibiting clinical signs. ANIMALS: Fifteen female New Zealand domestic rabbits with otitis due to naturally occurring infestation with P. cuniculi. METHODS: The external ears and ear canals of each individual were examined; samples of otic exudate were extracted with cotton swabs and examined microscopically for identification of the ectoparasite. Each animal was treated with a single 25 mg/kg oral dose of fluralaner. The amount of otic exudate/cerumen was assessed and samples were obtained from the ears to evaluate for presence or absence of mites at 4, 8, 12, 16, 20, 40 and 90 days after receiving treatment. RESULTS: Post-treatment, the amount of otic exudate decreased rapidly in all animals; by Day 12 and until the end of the study all rabbits were judged to have low amount of exudate with normally visible canals. The percentage of ears positive for P. cuniculi decreased to 13.3% of ears sampled by Day 4, and by Day 12 all rabbits were negative for the parasite. CONCLUSION: Administration of a single oral dose of fluralaner was effective for the treatment of naturally occurring P. cuniculi infestation in rabbits during a 90 day period.

Considering chance in quality and safety performance measures: an analysis of performance reports by boards in English NHS trusts.

OBJECTIVES: Hospital board members are asked to consider large amounts of quality and safety data with a duty to act on signals of poor performance. However, in order to do so it is necessary to distinguish signals from noise (chance). This article investigates whether data in English National Health Service (NHS) acute care hospital board papers are presented in a way that helps board members consider the role of chance in their decisions. METHODS: Thirty English NHS trusts were selected at random and their board papers retrieved. Charts depicting quality and safety were identified. Categorical discriminations were then performed to document the methods used to present quality and safety data in board papers, with particular attention given to whether and how the charts depicted the role of chance, that is, by including control lines or error bars. RESULTS: Thirty board papers, containing a total of 1488 charts, were sampled. Only 88 (6%) of these charts depicted the role of chance, and only 17 of the 30 board papers included any charts depicting the role of chance. Of the 88 charts that attempted to represent the role of chance, 16 included error bars and 72 included control lines. Only 6 (8%) of the 72 control charts indicated where the control lines had been set (eg, 2 vs 3 SDs). CONCLUSIONS: Hospital board members are expected to consider large amounts of information. Control charts can help board members distinguish signals from noise, but often boards are not using them. We discuss demand-side and supply-side barriers that could be overcome to increase use of control charts in healthcare.

Residual infestation and recolonization during urban Triatoma infestans Bug Control Campaign, Peru.

Chagas disease vector control campaigns are being conducted in Latin America, but little is known about medium-term or long-term effectiveness of these efforts, especially in urban areas. After analyzing entomologic data for 56,491 households during the treatment phase of a Triatoma infestans bug control campaign in Arequipa, Peru, during 2003-2011, we estimated that 97.1% of residual infestations are attributable to untreated households. Multivariate models for the surveillance phase of the campaign obtained during 2009-2012 confirm that nonparticipation in the initial treatment phase is a major risk factor (odds ratio [OR] 21.5, 95% CI 3.35-138). Infestation during surveillance also increased over time (OR 1.55, 95% CI 1.15-2.09 per year). In addition, we observed a negative interaction between nonparticipation and time (OR 0.73, 95% CI 0.53-0.99), suggesting that recolonization by vectors progressively dilutes risk associated with nonparticipation. Although the treatment phase was effective, recolonization in untreated households threatens the long-term success of vector control.

The effects of city streets on an urban disease vector.

With increasing urbanization vector-borne diseases are quickly developing in cities, and urban control strategies are needed. If streets are shown to be barriers to disease vectors, city blocks could be used as a convenient and relevant spatial unit of study and control. Unfortunately, existing spatial analysis tools do not allow for assessment of the impact of an urban grid on the presence of disease agents. Here, we first propose a method to test for the significance of the impact of streets on vector infestation based on a decomposition of Moran's spatial autocorrelation index; and second, develop a Gaussian Field Latent Class model to finely describe the effect of streets while controlling for cofactors and imperfect detection of vectors. We apply these methods to cross-sectional data of infestation by the Chagas disease vector Triatoma infestans in the city of Arequipa, Peru. Our Moran's decomposition test reveals that the distribution of T. infestans in this urban environment is significantly constrained by streets (p<0.05). With the Gaussian Field Latent Class model we confirm that streets provide a barrier against infestation and further show that greater than 90% of the spatial component of the probability of vector presence is explained by the correlation among houses within city blocks. The city block is thus likely to be an appropriate spatial unit to describe and control T. infestans in an urban context. Characteristics of the urban grid can influence the spatial dynamics of vector borne disease and should be considered when designing public health policies.

[Hemoglobin levels in pregnant women seen in health care centers of the Peruvian Ministry of Health, 2011]. / Niveles de hemoglobina en gestantes atendidas en establecimientos del Ministerio de Salud del Perú, 2011.

OBJECTIVES: Determine hemoglobin levels and prevalence of anemia in pregnant women seen in health care centers of the Ministry of Health at national level. MATERIALS AND METHODS: Cross-cut study where the database of the Information System on the Nutritional Health of Children under 5 and Pregnant Women (SIEN) were analyzed. 287 691 records of pregnant women examined at the health care centers of the Peruvian Ministry of Health in 2011 were included, hemoglobin levels corrected by height, age, gestational age, altitude and prevalence of anemia (light, moderate and serious) were analyzed. Descriptive statistics and the chi-square method were used. RESULTS: Nationwide prevalence of anemia in pregnant women was 28.0%, with mild anemia being at 25.1%, moderate anemia at 2.6% and severe anemia at 0.2%. Hemoglobin levels are higher in older and younger women during the first months of pregnancy, prevalence of anemia decreases with altitude. Furthermore, prevalence is higher in the Highland regions. Huancavelica was the region with higher prevalence of anemia (53.6%), followed by Puno with 51.0%. CONCLUSIONS: Hemoglobin levels get higher as the mother gets older, and they go down in keeping with the gestation trimester and altitude. Huancavelica has the highest prevalence of anemia in pregnant women.

Niveles de hemoglobina en gestantes atendidas en establecimientos del Ministerio de Salud del Perú, 2011 / Hemoglobin levels in pregnant women seen in health care centers of the peruvian ministry of health, 2011

Objetivos. Determinar los niveles de hemoglobina y la prevalencia de anemia en gestantes atendidas en los establecimientos del Ministerio de Salud a nivel nacional. Materiales y métodos. Estudio transversal donde se analizó la base de datos del Sistema de Información del Estado Nutricional del Niño menor de 5 años y de la Gestante (SIEN). Se incluyó 287 691 registros de gestantes evaluadas en establecimientos del Ministerio de Salud del Perú en 2011, se analizaron los niveles de hemoglobina corregida a la altura, edad, edad gestacional, altitud a nivel del mar y prevalencia de anemia (leve, moderada y grave). Se aplicaron estadísticas descriptivas y chi cuadrado. Resultados. La prevalencia a nivel nacional de anemia en la gestante fue de 28,0% siendo anemia leve de 25,1%, moderada de 2,6% y grave de 0,2%. Los niveles de hemoglobina son mayores en mujeres con mayor edad y menores durante los primeros meses de gestación, la frecuencia de anemia decrece con la altitud. Asimismo, la prevalencia es mayor en departamentos de la sierra. Huancavelica fue el departamento con mayor prevalencia de anemia (53,6%), seguido de Puno con 51,0%. Conclusiones. Los niveles de hemoglobina son mayores conforme la edad materna es mayor, y menores conforme el trimestre de gestación y altitud. Huancavelica tiene la mayor prevalencia de anemia en gestantes.

Objectives. Determine hemoglobin levels and prevalence of anemia in pregnant women seen in health care centers of the Ministry of Health at national level. Materials and methods. Cross-cut study where the database of the Information System on the Nutritional Health of Children under 5 and Pregnant Women (SIEN) were analyzed. 287 691 records of pregnant women examined at the health care centers of the Peruvian Ministry of Health in 2011 were included, hemoglobin levels corrected by height, age, gestational age, altitude and prevalence of anemia (light, moderate and serious) were analyzed. Descriptive statistics and the chi-square method were used. Results. Nationwide prevalence of anemia in pregnant women was 28.0%, with mild anemia being at 25.1%, moderate anemia at 2.6% and severe anemia at 0.2%. Hemoglobin levels are higher in older and younger women during the first months of pregnancy, prevalence of anemia decreases with altitude. Furthermore, prevalence is higher in the Highland regions. Huancavelica was the region with higher prevalence of anemia (53.6%), followed by Puno with 51.0%. Conclusions. Hemoglobin levels get higher as the mother gets older, and they go down in keeping with the gestation trimester and altitude. Huancavelica has the highest prevalence of anemia in pregnant women.

A field trial of alternative targeted screening strategies for Chagas disease in Arequipa, Peru.

BACKGROUND: Chagas disease is endemic in the rural areas of southern Peru and a growing urban problem in the regional capital of Arequipa, population ∼860,000. It is unclear how to implement cost-effective screening programs across a large urban and periurban environment. METHODS: We compared four alternative screening strategies in 18 periurban communities, testing individuals in houses with 1) infected vectors; 2) high vector densities; 3) low vector densities; and 4) no vectors. Vector data were obtained from routine Ministry of Health insecticide application campaigns. We performed ring case detection (radius of 15 m) around seropositive individuals, and collected data on costs of implementation for each strategy. RESULTS: Infection was detected in 21 of 923 (2.28%) participants. Cases had lived more time on average in rural places than non-cases (7.20 years versus 3.31 years, respectively). Significant risk factors on univariate logistic regression for infection were age (OR 1.02; p = 0.041), time lived in a rural location (OR 1.04; p = 0.022), and time lived in an infested area (OR 1.04; p = 0.008). No multivariate model with these variables fit the data better than a simple model including only the time lived in an area with triatomine bugs. There was no significant difference in prevalence across the screening strategies; however a self-assessment of disease risk may have biased participation, inflating prevalence among residents of houses where no infestation was detected. Testing houses with infected-vectors was least expensive. Ring case detection yielded four secondary cases in only one community, possibly due to vector-borne transmission in this community, apparently absent in the others. CONCLUSIONS: Targeted screening for urban Chagas disease is promising in areas with ongoing vector-borne transmission; however, these pockets of epidemic transmission remain difficult to detect a priori. The flexibility to adapt to the epidemiology that emerges during screening is key to an efficient case detection intervention. In heterogeneous urban environments, self-assessments of risk and simple residence history questionnaires may be useful to identify those at highest risk for Chagas disease to guide diagnostic efforts.

Retracing micro-epidemics of Chagas disease using epicenter regression.

Vector-borne transmission of Chagas disease has become an urban problem in the city of Arequipa, Peru, yet the debilitating symptoms that can occur in the chronic stage of the disease are rarely seen in hospitals in the city. The lack of obvious clinical disease in Arequipa has led to speculation that the local strain of the etiologic agent, Trypanosoma cruzi, has low chronic pathogenicity. The long asymptomatic period of Chagas disease leads us to an alternative hypothesis for the absence of clinical cases in Arequipa: transmission in the city may be so recent that most infected individuals have yet to progress to late stage disease. Here we describe a new method, epicenter regression, that allows us to infer the spatial and temporal history of disease transmission from a snapshot of a population's infection status. We show that in a community of Arequipa, transmission of T. cruzi by the insect vector Triatoma infestans occurred as a series of focal micro-epidemics, the oldest of which began only around 20 years ago. These micro-epidemics infected nearly 5% of the community before transmission of the parasite was disrupted through insecticide application in 2004. Most extant human infections in our study community arose over a brief period of time immediately prior to vector control. According to our findings, the symptoms of chronic Chagas disease are expected to be absent, even if the strain is pathogenic in the chronic phase of disease, given the long asymptomatic period of the disease and short history of intense transmission. Traducción al español disponible en Alternative Language Text S1/A Spanish translation of this article is available in Alternative Language Text S1.

A history of chagas disease transmission, control, and re-emergence in peri-rural La Joya, Peru.

BACKGROUND: The history of Chagas disease control in Peru and many other nations is marked by scattered and poorly documented vector control campaigns. The complexities of human migration and sporadic control campaigns complicate evaluation of the burden of Chagas disease and dynamics of Trypanosoma cruzi transmission. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a cross-sectional serological and entomological study to evaluate temporal and spatial patterns of T. cruzi transmission in a peri-rural region of La Joya, Peru. We use a multivariate catalytic model and Bayesian methods to estimate incidence of infection over time and thereby elucidate the complex history of transmission in the area. Of 1,333 study participants, 101 (7.6%; 95% CI: 6.2-9.0%) were confirmed T. cruzi seropositive. Spatial clustering of parasitic infection was found in vector insects, but not in human cases. Expanded catalytic models suggest that transmission was interrupted in the study area in 1996 (95% credible interval: 1991-2000), with a resultant decline in the average annual incidence of infection from 0.9% (95% credible interval: 0.6-1.3%) to 0.1% (95% credible interval: 0.005-0.3%). Through a search of archival newspaper reports, we uncovered documentation of a 1995 vector control campaign, and thereby independently validated the model estimates. CONCLUSIONS/SIGNIFICANCE: High levels of T. cruzi transmission had been ongoing in peri-rural La Joya prior to interruption of parasite transmission through a little-documented vector control campaign in 1995. Despite the efficacy of the 1995 control campaign, T. cruzi was rapidly reemerging in vector populations in La Joya, emphasizing the need for continuing surveillance and control at the rural-urban interface.

Autonomic dysfunction and risk factors associated with Trypanosoma cruzi infection among children in Arequipa, Peru.

Chagas disease affects an estimated 8 million people in Latin America. Infected individuals have 20-30% lifetime risk of developing cardiomyopathy, but more subtle changes in autonomic responses may be more frequent. We conducted a matched case-control study of children in Arequipa, Peru, where triatomine infestation and Trypanosoma cruzi infection are emerging problems. We collected data on home environment, history, physical examination, electrocardiogram, and autonomic testing. Signs of triatomine infestation and/or animals sleeping in the child's room and household members with Chagas disease were associated with increased infection risk. Electrocardiogram findings did not differ between cases and controls. However, compared with control children, infected children had blunted autonomic responses by three different measures, the Valsalva maneuver, the cold pressor test, and the orthostatic test. T. cruzi-infected children show autonomic dysfunction, although the prognostic value of this finding is not clear. Sustained vector control programs are essential to decreasing future T. cruzi infections.

Rational spatio-temporal strategies for controlling a Chagas disease vector in urban environments.

The rational design of interventions is critical to controlling communicable diseases, especially in urban environments. In the case of the Chagas disease vector Triatoma infestans, successful control is stymied by the return of the insect after the effectiveness of the insecticide wanes. Here, we adapt a genetic algorithm, originally developed for the travelling salesman problem, to improve the spatio-temporal design of insecticide campaigns against T. infestans, in a complex urban environment. We find a strategy that reduces the expected instances of vector return 34-fold compared with the current strategy of sequential insecticide application to spatially contiguous communities. The relative success of alternative control strategies depends upon the duration of the effectiveness of the insecticide, and it shows chaotic fluctuations in response to unforeseen delays in a control campaign. We use simplified models to analyse the outcomes of qualitatively different spatio-temporal strategies. Our results provide a detailed procedure to improve control efforts for an urban Chagas disease vector, as well as general guidelines for improving the design of interventions against other disease agents in complex environments.